Mavrilimumab to Reduce Progression of Acute Respiratory Failure in COVID-19 Pneumonia and Systemic Hyper-inflammation

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT04399980
• Collaborator: Kiniksa Pharmaceuticals, Ltd. (Industry)
• Enrollment: 40
• Locations: 2
• Arms: 2
• Actual Duration (Months): 11.1
• Patients Per Site: 20
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this prospective, Phase 2, multicenter, blinded, randomized placebo controlled study is to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe COVID-19 pneumonia and clinical and biological features of hyper-inflammation.

Condition or Disease	Intervention/Treatment	Phase
COVID 19; SARS-CoV 2; Pneumonia	Drug: Mavrilimumab; Drug: Placebos	Phase 2

Detailed Description

This prospective, Phase 2, multi-center, blinded randomized placebo-controlled study is designed to demonstrate that early treatment with mavrilimumab prevents progression of respiratory failure in patients with severe Covid-19 pneumonia and clinical and biological features of hyper-inflammation.

The study population includes patients who have severe pneumonia, defined as hospitalization due to Covid-19 with abnormal chest imaging and SpO2 <92% on room air or requirement for supplemental oxygen.

Enrollment: The study will be performed in approximately 4 months total, starting from the first patient enrolled with enrollment expected to complete within 2 months.

Follow-up period: The follow-up period is 60 days for each patient enrolled.

A total of 60 patients will be randomized using a 1:1 allocation ratio: 30 subjects will receive mavrilimumab, and 30 subjects will receive placebo infusion. The investigator, clinical team, and subject will be blinded to treatment assignment.

Participants will be identified by regular review of hospitalized COVID19 patients to evaluate for inclusion and exclusion criteria. Participants will then be approached in the standard manner by study investigator and coordinator/research nurse.

Research interventions will take place in the hospital in accordance with privacy standards.

The study team is informed on all study procedures and requirements with daily meetings and the opportunity to continuously update through secure channels.

In this multicenter consortium, each participating site will have their own IND for patients enrolled at their site. Data collection will occur at each of the 4 academic centers, and data analysis and randomization scheme will be performed by one site, Cleveland Clinic C5 Research.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Mavrilimumab to Reduce Progression of Acute Respiratory Failure in Patients With Severe COVID-19 Pneumonia and Systemic Hyper-inflammation
• Actual Study Start Date: May 20, 2020
• Actual Primary Completion Date: Apr 23, 2021
• Actual Study Completion Date: Apr 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intervention Treatment infusion	Drug: Mavrilimumab; Treatment infusion; Other Names: KPL-301
Placebo Comparator: Control Placebo infusion	Drug: Placebos; Placebo infusion; Other Names: Control

Outcome Measures

Primary Outcome Measures

1. Subjects Alive and Off of Oxygen at Day 14 [Day 14]

   Number and percentage of subjects alive and off of oxygen at day 14

Secondary Outcome Measures

1. Number of Subjects Alive and Without Respiratory Failure at Day 28 [Day 28]

   Number and percentage of subjects that are alive and without respiratory failure at Day 28

2. Mortality at Day 28 [Day 28]

   Number and percentage of patients that expired by Day 28

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria (must meet all):

1. Written informed consent must be obtained before any assessment is performed

2. Documented COVID19 pneumonia defined as positive SARS-CoV2 test AND abnormalities/ infiltrates on chest x-ray or computed tomography AND active fever or documented fever within 24-48 hours or ongoing anti-pyretic use to suppress fever

3. Hypoxia (Room air SpO2 <92% or requirement for supplemental oxygen)

4. Increased serum inflammatory marker (CRP > 5 mg/dL)

5. Severity of disease warrants inpatient hospitalization

Exclusion Criteria:

1. Onset of COVID-19 symptoms >14 days

2. Age < 18 years-old

3. Hospitalized >7 days

4. Mechanically ventilated

5. Serious concomitant illness which in the opinion of the investigator precludes the patient from enrolling in the trial, including (but not limited to):

• History of immunodeficiency (congenital or acquired)

• Neutropenia (absolute neutrophil count <1,500/mm3)

• History of solid-organ or bone marrow transplant

• History of current systemic autoimmune or autoinflammatory disease(s) requiring systemic immune-modulating drugs

• History of myeloproliferative disorder or active malignancy receiving cytotoxic chemotherapy

• Pre-existing severe pulmonary disease (i.e. steroid dependent asthma, COPD on home oxygen, or other restrictive/obstructive lung disease requiring home oxygen)

• Pre-existing severe left ventricular systolic dysfunction (i.e. LVEF <35%)

• Known or suspected active tuberculosis (TB), latent TB, or history of incompletely treated TB or at high risk for latent TB (from exposure or prior incarceration)

• History of active or latent viral hepatitis (i.e. Hepatitis B or C)

• Concomitant uncontrolled systemic bacterial or fungal infection

• Concomitant viral infection other than COVID-19 (e.g. Influenza, other respiratory viruses)

• History of chronic liver disease with portal hypertension

• History of end-stage renal disease on chronic renal replacement therapy

1. Recent treatment with cell-depleting biological therapies (e.g., anti-CD20) within 12 months, cell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-Interleukin [IL]-6 receptor [e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer), treatment with alkylating agents within 12 weeks, treatment with cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks

2. Recent treatment with intramuscular live (attenuated) vaccine within 4 weeks

3. Chronic or recent corticosteroid use > 10 mg/day

4. Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue breast-feeding during therapy taking into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother

5. Enrolled in another investigational study using immunosuppressive therapy

6. Known hypersensitivity to mavrilimumab or any of its excipients

7. In the opinion of the investigator, unable to comply with the requirements to participate in the study

8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug. Such methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

• Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject

• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Florida	Weston	Florida	United States	33331
2	Cleveland Clinic Health System	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic
• Kiniksa Pharmaceuticals, Ltd.

Investigators

• Principal Investigator: Paul C Cremer, M. D., The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 25, 2020

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT04399980
• Other Study ID Numbers: IND 149324; IRB 20-523
• First Posted: May 22, 2020
• Last Update Posted: May 13, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Pneumonia; Respiratory Insufficiency; Inflammation; Mavrilimumab

Study Results

Participant Flow

Arm/Group Title	Intervention	Control
Arm/Group Description	One-time Mavrilimumab infusion at 6mg/kg via IV	One-time placebo infusion via IV
Period Title: Overall Study
STARTED	21	19
COMPLETED	21	19
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Intervention	Control	Total
Arm/Group Description	One-time Mavrilimumab infusion at 6mg/kg via IV	One-time placebo infusion via IV	Total of all reporting groups
Overall Participants	21	19	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (13.49)	54.8 (18.44)	55.75 (15.97)
Sex: Female, Male (Count of Participants)
Female	7 33.3%	7 36.8%	14 35%
Male	14 66.7%	12 63.2%	26 65%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 38.1%	8 42.1%	16 40%
White	11 52.4%	8 42.1%	19 47.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 9.5%	3 15.8%	5 12.5%
Region of Enrollment (Count of Participants)
United States	21 100%	19 100%	40 100%
History of Diabetes (Count of Participants)
Count of Participants [Participants]	8 38.1%	9 47.4%	17 42.5%
History of Hypertension (Count of Participants)
Count of Participants [Participants]	10 47.6%	12 63.2%	22 55%
History of Hyperlipidemia (Count of Participants)
Count of Participants [Participants]	7 33.3%	11 57.9%	18 45%

Outcome Measures

1. Primary Outcome

Title	Subjects Alive and Off of Oxygen at Day 14
Description	Number and percentage of subjects alive and off of oxygen at day 14
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	One-time Mavrilimumab infusion at 6mg/kg via IV	One-time placebo infusion via IV
Measure Participants	21	19
Count of Participants [Participants]	12 57.1%	9 47.4%

2. Secondary Outcome

Title	Number of Subjects Alive and Without Respiratory Failure at Day 28
Description	Number and percentage of subjects that are alive and without respiratory failure at Day 28
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	One-time Mavrilimumab infusion at 6mg/kg via IV	One-time placebo infusion via IV
Measure Participants	21	19
Count of Participants [Participants]	20 95.2%	15 78.9%

3. Secondary Outcome

Title	Mortality at Day 28
Description	Number and percentage of patients that expired by Day 28
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	One-time Mavrilimumab infusion at 6mg/kg via IV	One-time placebo infusion via IV
Measure Participants	21	19
Count of Participants [Participants]	1 4.8%	3 15.8%

Adverse Events

Time Frame	60 days
Arm/Group Title	Intervention		Control
Arm/Group Description	One-time Mavrilimumab infusion at 6kg/mg via IV		One-time placebo infusion via IV
All Cause Mortality
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		4/19 (21.1%)
Serious Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/21 (23.8%)		4/19 (21.1%)
General disorders
Nausea	1/21 (4.8%)	1	0/19 (0%)	0
Shock	1/21 (4.8%)	1	0/19 (0%)	0
Investigations
Elevated WBC	0/21 (0%)	0	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome	3/21 (14.3%)	3	2/19 (10.5%)	2
Pneumonia	2/21 (9.5%)	2	1/19 (5.3%)	1
Chronic Respiratory Failure	0/21 (0%)	0	1/19 (5.3%)	1
Hypoxia - Worsening	2/21 (9.5%)	2	3/19 (15.8%)	3
Other (Not Including Serious) Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/21 (57.1%)		8/19 (42.1%)
Blood and lymphatic system disorders
anemia	2/21 (9.5%)	2	2/19 (10.5%)	2
Pulmonary Embolism	2/21 (9.5%)	2	1/19 (5.3%)	1
Clot	1/21 (4.8%)	1	1/19 (5.3%)	1
Cardiac disorders
Arrhythmia	0/21 (0%)	0	2/19 (10.5%)	2
Hypotension	0/21 (0%)	0	1/19 (5.3%)	1
General disorders
Headache	0/21 (0%)	0	1/19 (5.3%)	1
Shock	2/21 (9.5%)	2	1/19 (5.3%)	1
Hepatobiliary disorders
Liver Dysfunction	3/21 (14.3%)	3	0/19 (0%)	0
Worsening D Dimer	0/21 (0%)	0	1/19 (5.3%)	1
Infections and infestations
Fever	0/21 (0%)	0	1/19 (5.3%)	1
Investigations
Hypophosphatemia	1/21 (4.8%)	1	0/19 (0%)	0
Elevated Ferritin	0/21 (0%)	0	1/19 (5.3%)	1
Elevated CRP	0/21 (0%)	0	1/19 (5.3%)	1
Nervous system disorders
Delirium	1/21 (4.8%)	1	1/19 (5.3%)	1
Renal and urinary disorders
Acute Kidney Injury	4/21 (19%)	4	3/19 (15.8%)	3
Respiratory, thoracic and mediastinal disorders
Pneumonia	3/21 (14.3%)	3	2/19 (10.5%)	2
Acute Respiratory Syndrome	3/21 (14.3%)	3	4/19 (21.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.